Bindarit|130641-38-2|安捷凯

Background

Bindarit (2-methyl-2-[(1-[phenylmethyl]-1H-indazol-3yl) methoxy] propanoic acid) is a small molecule that is able to prevent the chronicity of inflammation and thus decrease the cytotoxic effects of inflammation as well as inhibit the synthesis of C–C chemokines including CCL2, CCL7, and CCL8. Treatment of Bindarit has been shown to lead to a dramatic reduction of urinary CCL2 and albumin excretion.^[1]

In vitro study indicated that Bindarit selectively inhibited the production of the monocyte chemotactic protein subfamily of CC inflammatory chemokines (MCP-1/CCL2) at the transcriptional level. Other in vitro research also showed that Bindarit exerted a concentration-related neuroprotective activity against both Aβ25-35 and Aβ1-42 toxicity. Specifically, in cultures of mixed cortical neural cells, Bindarit reduced Aβ-related neurotoxicity in a dose-dependent manner. This effect correlated with CCL2 suppression at both mRNA and protein level.^[2]

In vivo study demonstrated that Bindarit limited MCP-1/CCL2 upregulation in the kidney of PCK rats and that inhibition of the chemotactic signal translated in a reduced accumulation of inflammatory cells in the kidney. In vitro studies in murine podocytes exposed to albumin overload were instrumental to establish that amelioration of podocyte structure and antiproteinuric effect by Bindarit in PCK rats could be ascribed to drug’s ability of inhibiting podocyte MCP-1/ CCL2 production.^[3]

参考文献:
[1]. Shen Z, et al. Inhibition of CCL2 by Bindarit alleviates diabetes-associated periodontitis by suppressing inflammatory monocyte infiltration and altering macrophage properties. Cell Mol Immunol. 2021 Sep;18(9):2224-2235.
[2]. Severini C, et al. Bindarit, inhibitor of CCL2 synthesis, protects neurons against amyloid-β-induced toxicity. J Alzheimers Dis. 2014;38(2):281-93.
[3]. Zoja C, et al. Effects of MCP-1 inhibition by Bindarit therapy in a rat model of polycystic kidney disease. Nephron. 2015;129(1):52-61.

Bindarit (2-methyl-2-[(1-[phenylmethyl]-1H-indazol-3yl) methoxy] propanoic acid) 是一种小分子，能够预防慢性炎症，从而降低炎症的细胞毒性作用炎症以及抑制 C-C 趋化因子的合成，包括 CCL2、CCL7 和 CCL8。 Bindarit 的治疗已被证明可显着减少尿 CCL2 和白蛋白排泄。^[1]

体外研究表明，Bindarit 在转录水平选择性地抑制 CC 炎症趋化因子 (MCP-1/CCL2) 的单核细胞趋化蛋白亚家族的产生。其他体外研究还表明，Bindarit 对 Aβ25-35 和 Aβ1-42 毒性具有浓度相关的神经保护活性。具体来说，在混合皮层神经细胞的培养物中，Bindarit 以剂量依赖的方式降低了 Aβ 相关的神经毒性。这种效应与 mRNA 和蛋白质水平的 CCL2 抑制相关。^[2]

体内研究表明，Bindarit 限制了 PCK 大鼠肾脏中 MCP-1/CCL2 的上调，并且趋化信号的抑制转化为肾脏中炎症细胞积聚的减少。小鼠足细胞暴露于白蛋白超载的体外研究有助于确定 Bindarit 对 PCK 大鼠足细胞结构的改善和抗蛋白尿作用可归因于药物抑制足细胞 MCP-1/CCL2 产生的能力。^{[3]< /sup>}

Protocol

Cell experiment [1]:

Cell lines

M2 macrophage

Preparation Method

Macrophages (2 × 10⁵) were sorted out from the peripheral blood of bone-cancer mice and treated with different concentrations of bindarit after IL-4 stimulation.

Reaction Conditions

Treat macrophages with 0, 200, and 400 μM bindarit at 0, 2, and 6h after IL-4 stimulation.

Applications

Bindarit significantly inhibited M2 macrophage polarization in vitro. Treatment of bindarit significantly decreased the level of Arg1 mRNA and functioned in a dose-dependent manner. mRNA levels of other M2 macrophage polarization markers Ym1, Mrc1, and Fizz1 were also down-regulated after bindarit treatment. Bindarit also inhibits phosphorylation of both IκBα and p65.

Animal experiment [1]:

Animal models

Adult male athymic nude mice, 7–8 weeks old, weighing 25–30 g

Preparation Method

Mice received an intraperitoneal inoculation of breast sarcocarcinoma Walker 256 cells. Bone cancer was then established by inoculating Walker 256 cells (2 × 10⁵ cells, 10 μL) into the intramedullary space of the mouse femur. Control mice (n = 20) were injected with heat-killed cancer cells.

Dosage form

100 mg/kg

Applications

Bindarit exhibited protective effect against bone-cancer-induced pain and inflammation. Treatment of bindarit also significantly improved the performance of the mice in spontaneous nocifensive behavior test and in mechanical hyperalgesia test, suggesting that treatment of bindarit significantly relieves the pain caused by bone cancer. Bindarit also reduced monocyte mobilization in peripheral blood.

参考文献:

[1]. Liu S, et al. Bindarit Attenuates Pain and Cancer-Related Inflammation by Influencing Myeloid Cells in a Model of Bone Cancer. Arch Immunol Ther Exp (Warsz). 2018 Jun;66(3):221-229.

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